Glycogen Synthase Kinase-3 (GSK-3) Inhibitory Activity and Structure–Activity Relationship (SAR) Studies of the Manzamine Alkaloids. Potential for Alzheimer’s Disease

Abstract

Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3beta inhibitors. The semisynthesis of new analogues and the first structure-activity relationship studies with GSK-3beta are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3beta, specifically CDK-1, PKA, CDK-5, MAPK, and GSK-3alpha, show the specific inhibition of manzamine A on GSK-3beta and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer's disease.